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Modern Methods in Stereoselective AldolReactions
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Edited by Rainer Mahrwald
Modern Methods in Stereoselective AldolReactions
The Editor
Prof. Dr. Rainer MahrwaldHumboldt-Universitat BerlinInstitut fur ChemieBrook-Taylor-Str. 212489 Berlin
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V
Contents
Preface XIList of Contributors XIII
1 Stereoselective Acetate Aldol Reactions 1Pedro Romea and Felix Urpı
1.1 Introduction 11.2 Mukaiyama Aldol Reaction 21.2.1 Concept and Mechanism 21.2.2 Chiral Auxiliaries 41.2.3 Chiral Methyl Ketones 61.2.4 Chiral Aldehydes 81.2.4.1 1,2-Asymmetric Induction 81.2.4.2 1,3-Asymmetric Induction 131.2.4.3 Merged 1,2- and 1,3-Asymmetric Induction 171.2.5 Chiral Lewis Acids 221.2.6 Chiral Lewis Bases 351.3 Metal Enolates 411.3.1 Concept and Mechanism 411.3.2 Chiral Auxiliaries 421.3.3 Stoichiometric Lewis Acids 471.3.4 Catalytic Lewis Acids 481.3.5 Chiral Aldehydes 501.3.6 Chiral Methyl Ketones 551.3.6.1 α-Methyl Ketones 561.3.6.2 α-Hydroxy Ketones 571.3.6.3 β-Hydroxy Ketones 601.3.6.4 β-Hydroxy α-Methyl Ketones 631.3.6.5 α,β-Dihydroxy Ketones 641.3.6.6 Remote Stereocontrol 671.4 Conclusions 68
References 69
VI Contents
2 The Vinylogous Mukaiyama Aldol Reaction in Natural ProductSynthesis 83Martin Cordes and Markus Kalesse
2.1 Introduction 832.2 Aldehyde-Derived Silyl Dienol Ethers 842.2.1 Aldehyde-Derived Silyl Dienol Ethers – Diastereoselective
Processes 842.2.2 Aldehyde-Derived Silyl Dienol Ethers – Enantioselective Processes 872.3 Ester-Derived Silyl Dienol Ethers 902.3.1 Ester-Derived Silyl Dienol Ethers – Diastereoselective Processes 902.3.2 Ester-Derived Silyl Dienol Ethers – Enantioselective Processes 962.3.3 Ester-Derived Silyl Dienol Ethers – Enantioselective and
Substrate-Controlled Processes 1052.4 Amide-Derived Silyl Dienol Ethers – Vinylketene Silyl N,O-Acetals 1082.4.1 Model Systems – Kobayashi’s Pioneering Studies 1082.4.2 Total Syntheses 1092.5 Acyclic Acetoacetate-Derived Silyl Dienolates – Chan’s Diene 1172.5.1 Chan’s Diene in Diastereoselective Processes 1172.5.2 Chan’s Diene in Enantioselective Processes 1212.5.3 Chan’s Diene in Enantioselective and Substrate-Controlled
Processes 1222.6 Cyclic Acetoacetate-Derived Dienolates 1242.6.1 Cyclic Acetoacetate-Derived Dienolates – Diastereoselective
Processes 1242.6.2 Cyclic Acetoacetate-Derived Dienolates – Enantioselective
Processes 1262.6.3 Cyclic Acetoacetate-Derived Dienolates – Enantioselective and
Substrate-Controlled Processes 1322.7 Furan-Derived Silyloxy Dienes 1332.7.1 Furan-Derived Silyloxy Dienes – Diastereoselective Processes 1332.7.2 Furan-Derived Silyloxy Dienes – Enantioselective Processes 1382.7.3 Furan-Derived Silyloxy Dienes – Enantioselective and
Substrate-Controlled Processes 1412.8 Pyrrole-Based 2-Silyloxy Dienes 1422.9 Comparison with Other Methods 148
References 151
3 Organocatalyzed Aldol Reactions 155Gabriela Guillena
3.1 Introduction 1553.2 Proline as Organocatalyst 1563.2.1 Intramolecular Reactions 1563.2.1.1 Intramolecular Proposed Mechanism 1593.2.1.2 Application to Natural Product Synthesis 1613.2.2 Intermolecular Reactions 163
Contents VII
3.2.2.1 Ketones as Source of Nucleophile 1633.2.2.2 Aldehydes as Source of Nucleophile 1713.2.2.3 Intermolecular Reaction Mechanism 1753.2.2.4 Application to Natural Product Synthesis 1773.3 Proline Derivatives as Organocatalysts 1793.3.1 Prolinamide Derivatives 1803.3.1.1 Ketones as Source of Nucleophile 1803.3.1.2 Aldehydes as Source of Nucleophile 1973.3.1.3 Application to Natural Product Synthesis 1973.3.2 Proline Peptide Derivatives 1993.3.2.1 Ketones as Source of Nucleophile 1993.3.3 Hydroxyproline Derivatives 2053.3.3.1 Intramolecular Reactions 2053.3.3.2 Intermolecular Reactions 2073.3.4 Sulfonimide Proline Derivatives 2163.3.4.1 Ketones as Source of Nucleophile 2163.3.4.2 Application to Natural Product Synthesis 2193.3.5 Other Proline Derivatives 2203.3.5.1 Intramolecular Reactions 2203.3.5.2 Intermolecular Reactions 2213.3.5.3 Application to Natural Product Synthesis 2313.3.6 Other Organocatalysts 2333.3.6.1 Intramolecular Reactions 2333.3.6.2 Intermolecular Reactions 2353.3.7 Phase-Transfer Catalysis 2513.4 Conclusions and Outlook 253
References 253
4 Supersilyl Protective Groups in Aldol Reactions 269Patrick B. Brady and Hisashi Yamamoto
4.1 Introduction 2694.2 Aldol Addition with Acetaldehyde-Derived Super Silyl Enol
Ether (1) 2704.3 α-Substituted Silyl Enol Ethers Derived from Aldehydes 2704.4 Aldol Addition to Chiral Aldehydes 2724.5 One-Pot Sequential Aldol Reactions 2744.6 Sequential Aldol–Aldol Reactions of Acetaldehyde 2754.6.1 Acetaldehyde Double Aldol Reactions 2754.6.2 Acetaldehyde Triple Aldol Reactions 2754.6.3 Mixed Sequential Aldol–Aldol Reactions 2774.7 Double Aldol Reactions with α-Substituted Silyl Enol Ethers 2774.7.1 Sequential Aldol–Aldol Reactions with Mixed SEEs 2774.7.2 Propionaldehyde Aldol–Aldol Cascade Reactions 2794.7.3 Haloacetaldehyde Aldol–Aldol Cascades 2804.8 Stereochemical Considerations 281
VIII Contents
4.9 Aldol Reactions of β-Supersiloxy Methyl Ketones 2824.10 Total Synthesis of Natural Products Using Supersilyl Aldol
Reactions 2854.11 Conclusion and Outlook 288
References 288
5 Asymmetric Induction in Aldol Additions 293Luiz C. Dias, Ellen C. Polo, Emılio C. de Lucca Jr, and Marco A.B. Ferreira
5.1 Introduction 2935.2 Asymmetric Induction Using Chiral Ketones 2955.2.1 1,4-Asymmetric Induction Using α-Alkyl Ketones 2965.2.2 1,4-Asymmetric Induction Using α-Methyl-β-Branched Ketones 3025.2.3 1,4-Asymmetric Induction Using α-Alkoxy Ketones 3055.2.4 1,5-Asymmetric Induction Using β-Alkoxy Methyl Ketones 3135.2.5 1,6-Asymmetric Induction Using Chiral Methyl Ketones 3175.3 Asymmetric Induction Using Chiral Aldehydes 3175.3.1 1,2-Asymmetric Induction Using Chiral Aldehydes 3175.3.2 1,3-Asymmetric Induction Using Chiral Aldehydes 3355.3.3 Asymmetric Induction Using α-Methyl-β-Alkoxy Aldehydes 3425.3.4 Asymmetric Induction Using α,β-Bisalkoxy Aldehydes 3575.4 Asymmetric Induction in the Aldol Addition of Chiral Enolates to Chiral
Aldehydes 360References 371
6 Polypropionate Synthesis via Substrate-Controlled Stereoselective AldolCouplings of Chiral Fragments 377Dale E. Ward
6.1 Introduction 3776.2 Principles of Stereoselective Aldol Reactions 3786.2.1 Relative Topicity 3786.2.2 Chiral Reactants 3816.2.2.1 Diastereoface Selectivity of Chiral Ethyl Ketones 3816.2.2.2 Diastereoface Selectivity of Chiral Aldehydes 3866.2.2.3 Multiplicativity Rule 3946.3 Stereoselective Aldol Coupling of Chiral Reactants 3986.3.1 2-Alkoxy-1-Methylethyl Ethyl Ketones: Paterson’s Dipropionate
Equivalent 3986.3.1.1 Reactions with Achiral Aldehydes 3986.3.1.2 Reactions with Chiral Aldehydes 4006.3.2 1-Methylalkyl Ethyl Ketones: 3-Deoxy Polypropionate Equivalents 4026.4 2-Alkoxyalkyl Ethyl Ketones: 2-Desmethyl Polypropionate
Equivalents 4066.4.1 2-Alkoxy-1-Methylalkyl Ethyl Ketones: Polypropionate Equivalents 4096.4.1.1 (E) Boron Enolates 4116.4.1.2 (Z) Boron Enolates 412
Contents IX
6.4.1.3 Silyl Enolates 4136.4.1.4 Lithium Enolates 4146.4.1.5 Titanium Enolates 4166.4.1.6 Tin Enolates 4196.5 Conclusions 420
References 424
7 Application of Oxazolidinethiones and Thiazolidinethiones in AldolAdditions 431Michael T. Crimmins
7.1 Introduction 4317.2 Preparation of Oxazolidinethione and Thiazolidinethione Chiral
Auxiliaries 4317.3 Acylation of Oxazolidinethione and Thiazolidinethione Chiral
Auxiliaries 4337.4 Propionate Aldol Additions 4347.5 Acetate Aldol Additions 4377.6 Glycolate Aldol Additions 4437.6.1 Synthetic Applications of Aldol Additions of N-Propionyl
Oxazolidinethiones and Thiazolidinethiones and Their SubstitutedVariants 443
7.6.2 Synthetic Applications of Aldol Additions of N-Acetyloxazolidinethionesand Thiazolidinethiones 461
7.6.3 Synthetic Applications of anti-Aldol Additions ofN-Glycolyloxazolidinethiones 466References 471
8 Enzyme-Catalyzed Aldol Additions 475Pere Clapes and Jesus Joglar
8.1 Introduction 4758.2 Pyruvate Aldolases 4778.3 N-Acetylneuraminic Acid Aldolase (NeuA) 4788.3.1 Novel NeuA Biocatalyst by Protein Engineering 4828.3.2 Large-Scale Process 4868.3.3 Related Pyruvate Aldolases/2-Oxobutyrate Aldolases 4878.4 Dihydroxyacetone Phosphate (DHAP) Aldolases 4948.4.1 Structure and Mechanism 5008.4.2 L-Rhamnulose-1-Phosphate Aldolase as a DHA-Dependent
Aldolase 5028.5 D-Fructose-6-Phosphate Aldolase and Transaldolase B Phe178Tyr:
FSA-Like Aldolases 5038.6 2-Deoxy-D-Ribose-5-Phosphate Aldolase (RibA or DERA; EC
4.1.2.4) 5108.7 Glycine/Alanine Aldolases 5148.8 Aldol Reactions Catalyzed by Non aldolases 520
X Contents
8.9 Conclusions and Perspectives 5208.9.1 Substrate Tolerance/Stereoselectivity 5218.9.2 Future Perspectives 521
References 522
Index 529
XI
Preface
Stereoselectivity is one of the most important aspects for natural product chemists.Following the increasing possibility of detection and assignment of stereogeniccenters, a tremendous increase in stereoselective methods of organic reactions,particularly aldol reactions, has been noticed. In the beginning of this development,only sporadic examples of stereoselective aldol reactions were described, mostly inthe context of total syntheses of natural products. An outstanding early exampleis the R. B. Woodward’s proline-catalyzed aldol addition in the total synthesis oferythronolide A at the Harvard University in 1981. In the following three decades,a vast arsenal of stereoselective aldol additions has been developed (see Figure).
0
50
100
150
200
250
300
350
400
450Publications per year
19781981
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19901993
1996
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2008
This book provides a compre-hensive review of modern aldolreactions, especially in the aspectof how to achieve high stereos-electivity – diastereoselectivity aswell as enantioselectivity. Stereos-election is discussed under severaldifferent aspects. One aspect is thedeployment of different substrates –acetate or propionate aldol reactions.Another aspect is the mode of actionincluding metal enolate chemistry,Lewis acid as well as Lewis basecatalysis, enzymatic catalysis, andorganocatalysis. There are someoverlappings of these aspects in thechapters covering the cross-cuttingthemes of vinyloguos Mukaiyama reaction or asymmetric inductions (e.g., com-pare Scheme 1.50 with Scheme 2.59) or total synthesis of dolastatin 19 – (compareScheme 1.82 with Scheme 5.8). These overlappings, however, are intentional inorder to give a comprehensive insight into the techniques for installing requiredconfigurations during aldol reactions. The utility of the corresponding methodsis shown in the context of total syntheses of natural products. All chapters arethoroughly well written by experts in the respective fields.
XII Preface
It is my pleasure to express profound gratitude to the 15 authors for their hugeendeavor to organize and summarize this vast amount of material. It has been agreat pleasure for me to work with this team of authors at all times. Finally, myspecial thanks go to Elke Maase and Bernadette Gmeiner at WILEY for their finework in making this book a reality.
Berlin, Autumn 2012 Rainer Mahrwald
XIII
List of Contributors
Patrick B. BradyThe University of ChicagoDepartment of Chemistry5735 S. Ellis Ave. (GHJ 409)ChicagoIllinois 60637USA
Pere ClapesInstituto de Quımica Avanzada deCatalunaConsejo Superior deInvestigaciones Cientıficas(IQAC-CSIC)Departmento de QuımicaBiologica y ModelizacionMolecularJordi Girona 18-2608034 BarcelonaSpain
Martin CordesLeibniz Universitat HannoverCenter for Biomolecular DrugResearchSchneiderberg 1 B30167 HannoverGermany
Michael T. CrimminsUniversity of North Carolina atChapel HillKenan LaboratoriesChapel HillNC 27599USA
Luiz C. DiasUniversity of CampinasUNICAMPInstitute of ChemistryC.P. 615413083-970 CampinasSao PauloBrazil
Marco A. B. FerreiraUniversity of CampinasUNICAMPInstitute of ChemistryC.P. 615413083-970 CampinasSao PauloBrazil
XIV List of Contributors
Gabriela GuillenaUniversidad de AlicanteInstituto de Sintesis OrganicaDepartamento de QuimicaOrganicaApdo 9903080 AlicanteSpain
Jesus JoglarInstituto de Quımica Avanzada deCatalunaConsejo Superior deInvestigaciones Cientıficas(IQAC-CSIC)Departmento de QuımicaBiologica y ModelizacionMolecularJordi Girona 18-2608034 BarcelonaSpain
Markus KalesseLeibniz Universitat HannoverCenter for Biomolecular DrugResearchSchneiderberg 1 B30167 HannoverGermany
Emılio C. de Lucca Jr.University of CampinasUNICAMPInstitute of ChemistryC.P. 615413083-970 CampinasSao PauloBrazil
Ellen C. PoloUniversity of CampinasUNICAMPInstitute of ChemistryC.P. 615413083-970 CampinasSao PauloBrazil
Pedro RomeaUniversitat de BarcelonaDepartament de QuımicaOrganicaMartı i Franques 1–1108028 BarcelonaCataloniaSpain
Felix UrpıUniversitat de BarcelonaDepartament de QuımicaOrganicaMartı i Franques 1–1108028 BarcelonaCataloniaSpain
Dale E. WardUniversity of SaskatchewanDepartment of Chemistry110 Science PlaceSaskatoonSK S7N 5C9Canada
Hisashi YamamotoThe University of ChicagoDepartment of Chemistry5735 S. Ellis Ave. (GHJ 409)ChicagoIllinois 60637USA
1
1Stereoselective Acetate Aldol Reactions
Pedro Romea and Felix Urpı
1.1Introduction
The stereochemical control of aldol reactions from unsubstituted enol- or enolate-like species, what are known as acetate aldol reactions, has been a matter of concernfor nearly 30 years [1, 2]. Indeed, pioneering studies soon recognized that theasymmetric installation of a single stereocenter in such aldol reactions was muchmore demanding than the simultaneous construction of two new stereocenters inthe related propionate counterparts (Scheme 1.1) [3]. This challenge, together withthe ubiquitous presence of chiral β-hydroxy α-unsubstituted oxygenated structuresin natural products, has motivated the development of new concepts and strategiesand a large number of highly stereoselective methodologies. These involveLewis-acid-mediated additions of enolsilane derivatives of carbonyl compoundsto aldehydes (Mukaiyama aldol variant) [4, 5], a plethora of transformations thattake advantage of the reactivity of boron, titanium(IV), and tin(II) enolates (metalenolates) [6], and some insightful organocatalytic approaches [7]. In spite of theseaccomplishments, the quest for more powerful and selective methodologiesand a better understanding of their intricate mechanisms is an active area ofresearch. Herein, we describe the most significant achievements in the field ofstereoselective acetate aldol reactions based on the Lewis-acid-mediated additionof enolsilanes and metal enolates to aldehydes, with particular attention to theirapplication to the asymmetric synthesis of natural products. Recent advances inparallel organocatalytic procedures are not discussed.
R1 R2
O
R1
O
R
OH
Me
RCHO RCHO
R2: Me R2: H R1
O
R
OH
H
Propionate aldol reaction Acetate aldol reactionTwo new stereocenters A single new stereocenter
Four stereoisomers Two stereoisomers
Scheme 1.1 Aldol reactions.
Modern Methods in Stereoselective Aldol Reactions, First Edition. Edited by Mahrwald, R.© 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.
2 1 Stereoselective Acetate Aldol Reactions
1.2Mukaiyama Aldol Reaction
1.2.1Concept and Mechanism
With some significant exceptions, enolsilanes are unreactive toward aldehydes.1)
This lack of reactivity can be overcome by increasing the electrophilic characterof aldehydes or the nucleophilicity of enolsilanes. The former option is achievedby coordination of Lewis acids (MLn) to the carbonyl group, which enhancesthe electrophilicity of the C=O bond and facilitates the attack of enolsilanes.This represents the canonical Mukaiyama aldol variant ((1) in Scheme 1.2) [4,5]. It also covers vinylogous aldol transformations, which involve the reactionsof γ -unsubstituted β, γ -conjugated enolsilanes ((2) in Scheme 1.2) [8]. In turn,the latter option takes advantage of the activation of the nucleophilic character ofenolsilanes by binding of Lewis bases such as phosphoramides (O=P(NR2)3) to thesilicon atom ((3) in Scheme 1.2) [9].
Early mechanistic analyses suggested that Lewis-acid-mediated aldol reactionsrepresented in Scheme 1.2 proceeded through open transition states [4, 5, 10]. Thismodel assumes a transoid geometry for the Lewis-acid-aldehyde complex, which theenolsilane attacks following antiperiplanar or synclinal approaches, as representedin Scheme 1.3. Antiperiplanar transition states I and II are usually more favorablebecause of the minimization of dipolar interactions, the steric interactions betweenthe enolsilane (R1 or R3SiO groups) and the aldehyde (R2 group) being the mainsource of instability. Similar steric interactions arise in synclinal transition statesIII and IV, whereas V and VI are characterized by a destabilizing interactionbetween the enolsilane and the Lewis acid coordinated to the carbonyl oxygen.Then, steric and stereoelectronic interactions determine the relative stability of
+(1)
(2) +α
β
γ
β
R2 H
OMLn
R1
OSiR3
R1
O
R2
OH
R2
OH
R1
O
R2 H
OMLn
R1
OSiR3
+(3)R2 H
O
R1
O
R2
OH
R1
OSi
O=P(NR2)3
R3
Scheme 1.2 Mukaiyama aldol variants.
1) As silyl enolates derived from amides and trihalosilyl enolates.
1.2 Mukaiyama Aldol Reaction 3
H
R1
H
OSiR3
O
HR2
MLn
H
R3SiO
H
R1
O
HR2
MLn
H
H
R3SiO
R1
O
HR2
MLn
H
H
R1
R3SiO
O
HR2
MLn OSiR3
R1
H
HO
HR2
MLnR1
OSiR3
H
HO
HR2
MLn
Antiperiplanar approaches
Synclinal approaches
I II
III IV V VI
Scheme 1.3 Open transition states for Mukaiyama aldol reactions.
I–VI and the capacity to differentiate one from the other faces of the carbonylbond.
Despite the importance and utility of this paradigm, it is probably an oversim-plified model because it ignores the fate of the silyl group. In this respect, somemodels take into account the silicon moiety and suggest cyclic transition statesVII–IX, as represented in Scheme 1.4. Importantly, the role of the silyl group isnot limited to influencing the nature of the transition state, because the silicontransfer from the enolsilane to the β-alkoxy position may be a key step in the overallmechanism and becomes crucial to the turnover necessary for nonstoichiometrictransformations [11].
Irrespective of the mechanistic pathway, the asymmetric induction achievedby these Lewis-acid-mediated aldol reactions depends on chiral elements on theenolsilane (the nucleophilic partner), the aldehyde (the electrophilic partner), orthe Lewis acid (the activating element), so they must all cooperate to providethe appropriate face differentiation of the carbonyl bond in order to control theconfiguration of the new stereocenter. The influence of these elements is discussedin the following sections.
O
SiR3O
R1
H
R2
MLnO
MLnO
R1
H
R2
SiR3
O
SiOM
Lm
X
R1
H
R2
R3
VII VIII IX
Scheme 1.4 Cyclic transition states for Mukaiyama aldol reactions.
4 1 Stereoselective Acetate Aldol Reactions
1.2.2Chiral Auxiliaries
In the context of emergence of chiral auxiliaries as powerful platforms to achieveasymmetric transformations, Helmchen reported highly diastereoselective aldolreactions of chiral auxiliary-based silyl ketene acetals (1) and (2) [12, 13]. As shownin Scheme 1.5, TiCl4-mediated additions of 1 and 2 to isobutyraldehyde affordedaldol adducts 3 and 4 in good yields and excellent diastereomeric ratios, presumablythrough a chairlike transition state in which the titanium atom is simultaneouslycoordinated to the carbonyl and the OTBS group. In turn, these adducts can beconverted into the corresponding β-hydroxy acids in quantitative yield by simpletreatment with KOH in methanol.
This approach was quickly surpassed by alternative methodologies based onchiral aldehydes or Lewis acids and bases (Sections 1.2.4–1.2.6). Nevertheless,new findings restored the interest in this sort of transformations a few yearsago. Indeed, Kobayashi described highly stereoselective vinylogous Mukaiyamaaldol reactions using silyl vinyl ketene N,O-acetals prepared from valine-derived1,3-oxazolidin-2-ones [14]. As represented in Scheme 1.6, TiCl4-mediated addi-tions of α-methyl acetal (5) to aliphatic, α, β-unsaturated, and aromatic aldehydesafforded δ-hydroxy-α-methyl-α, β-unsaturated imides (6) in excellent yields anddiastereomeric ratios. Such outstanding remote asymmetric induction was be-lieved to arise from a conformation in which the chiral heterocycle is almostperpendicular to the dienol plane and the isopropyl group overhangs the up-per face of the dienol moiety. Then, the aldehyde approaches from the lesshindered face through an open transition state in which the α-methyl groupappears to be essential to achieve the observed high stereocontrol. Finally, thechiral auxiliary can be removed by well-known methodologies used for Evansauxiliaries.
ON
OTBS
SO2Ph
Ar
NSO2PhO
OTBS
Ar
+ i-PrCHO
dr 97 : 3
NSO2PhO
O
Ar
OH
1 equiv TiCl4
CH2Cl2, –80 °C+ i-PrCHO
dr 95 : 5
ONSO2Ph
O
Ar
OH
NSO2PhO
Ar
OCl4Ti O
i-PrHTBS
1 equiv TiCl4
CH2Cl2, –80 °C
Ar: 3,5-Me2Ph1 3
2 4Ar: 3,5-Me2Ph
62%
51%
Scheme 1.5 Chiral auxiliary-based Mukaiyama aldol reactions.
1.2 Mukaiyama Aldol Reaction 5
NO
O OTBS
NO
O O
R
OH1 equiv TiCl4
CH2Cl2, –78 °C+ RCHO
dr > 95 : 5 65–97%
5 6
Me
N
OTBS
HHH
O
O
MeMe
R
O
HH
H H
Me
Xc
OTBS
Cl4Ti
R: i-Pr, CH2R′, CH=CHR′, Ph
α α
γα
δ
β
ORHCl4Ti
Scheme 1.6 Chiral auxiliary-based vinylogous Mukaiyama aldol reactions.
This methodology was used for the construction of the AB ring of fomitellicacids (7) (Scheme 1.7) [15]. Initially, application of the standard conditions toent-5 and enal (8) provided the desired aldol (9), but the reaction was slow andhard to reproduce. Then, a thorough study of this particular reaction uncoveredsignificant rate enhancements by adding catalytic amounts of water in toluene,which permitted to obtain aldol (9) in 76% yield as a single diastereomer in astraightforward and consistent way [16]. The origin of this catalytic effect remainsunclear, but it has proved to be general and has been successfully applied to otheraldehydes [17].
NO
O OTBS
NO
O O OH
1 equiv TiCl4,10 mol% H2O+
ent-5
OTBDPS
H
O
OTBDPS
76%
PhCH3, – 50 °C
9
HO
HOH
OHO2C
7
8
Scheme 1.7 Synthesis of the central ring of fomitellic acids.
6 1 Stereoselective Acetate Aldol Reactions
OTBSTBSO
+ RCHO
OTBSO
R
OH OTBSO
R
OH1.5 equiv BF3·OEt2
CH2Cl2, –78 °C+
10 11 12
Ph
i-Pr
PhCH2CH2
PhCH=CH
60 : 40
50 : 50
36 : 64
33 : 67
R dr (11 : 12)
Scheme 1.8 Asymmetric induction imparted by a silyl enol ether from a chiral methylketone.
1.2.3Chiral Methyl Ketones
There are no systematic studies on the asymmetric induction imparted by chiralmethyl ketones. However, most of the examples reported so far suggest thatsubstrate-controlled Mukaiyama aldol reactions based on chiral methyl ketonesare poorly stereoselective. This lack of stereocontrol is well illustrated by the aldolreaction of chiral silyl enol ether (10), in which the major diastereomer, 11 or 12,depends on the achiral aldehyde (Scheme 1.8) [18].
In a more complex framework, De Brabander also reported that silyl enolethers from enantiomeric methyl ketones (13) and (ent-13) underwent additionsto chiral aldehyde (14) to afford the corresponding aldol adducts 15 and 16 insimilar yields (Scheme 1.9) [19]. Considering that the new C11-stereocenterspossess the same configuration in both adducts and that the diastereoselectivity is
CO2Me
OO
CO2Me
OO
(1)TMSOTf, 2,6-lutidine(2)1.3 equiv BF3·OEt2, CH2Cl2, –78 °C
OH
OO
OPMB
OMe
OO
CO2Me
OH
OO
OPMB
OMe
OO
CO2Me
O
H OO
OPMB
OMe14
13
ent-13
15
16
11
11dr 89 : 11 51%
dr 92 : 8 60%
Scheme 1.9 Chiral methyl ketones in stereoselective Mukaiyama aldol reactions.
1.2 Mukaiyama Aldol Reaction 7
dr > 89 : 1161–78%
OTMS
PivO
+ RCHO
O
PivO
R
OH
O Ti
OClSi
PivOHMe
R
TMS
Cl3H
1 equiv TiCl4
CH2Cl2, –78 °C
17 18R: n -C5H11, i -Pr, t-Bu
OTMS
OPG
O
OPG
OH
+ i-PrCHO
19
PG: PMB, TES
0.3 equiv BF3·OEt2
CH2Cl2, –78 °C
dr > 96 : 4 36% 20
(1)
(2)
Scheme 1.10 Asymmetric induction imparted by chiral α-hydroxy methyl ketones inMukaiyama aldol reactions.
comparable for both processes, it can be concluded that the asymmetric inductionprovided by the aldehyde is much more important than that provided by theketone.
Lactate-derived and other α-hydroxy methyl ketones are exceptions to this trend.Thus, Trost found that TiCl4-mediated aldol reactions of pivaloyl-protected silyl enolether (17) afforded β-hydroxy ketones (18) in high yields and diastereomeric ratiosup to 98 : 2 [20]. This was assumed to be achieved through an eight-membered cyclictransition state in which the titanium is simultaneously bound to the aldehyde andthe enolsilane ((1) in Scheme 1.10). Importantly, dipole–dipole interactions areunderstood to favor the antiperiplanar arrangement of the C–OPiv and the C–OSibonds and impel the aldehyde toward the less hindered face of the enolsilane.Moreover, Kalesse reported that parallel BF3-catalyzed additions of silyl enol ethers(19) to isobutyraldehyde afforded the corresponding aldols (20) with excellentdiastereoselectivity but in low yield ((2) in Scheme 1.10) [21]. The origin of suchremarkable stereocontrol is unclear.
At this point, it is worth mentioning that Yamamoto has also reported highlydiastereoselective Mukaiyama aldol reactions based on chiral β-tris(trimethylsilyl)silyloxy methyl ketones containing a single stereocenter at the β-position [22]. Thischemistry is discussed in connection with parallel methodologies (Sections 1.2.4and 1.3.6).
Finally, Ley reported that reactions of silyl enol ethers from chiralπ-allyltricarbonyliron lactone or lactam complexes proceeded with a significantremote stereocontrol [23]. This is illustrated by the BF3-mediated addition ofcomplexes 21 to benzaldehyde furnishing β-hydroxy ketones (22) with excellentdiastereomeric ratios (Scheme 1.11). The remarkable 1,7-induction provided bythese substrates is due to the chiral environment created on the lower face ofthe silyl enol ether (the upper face is blocked by the tricarbonyliron moiety) bythe endo-oriented methyl substituent at the sp3-stereocenter. Then, the incomingactivated aldehyde approaches in a synclinal arrangement in which unfavorablesteric interactions are minimized.
8 1 Stereoselective Acetate Aldol Reactions
OTMSX
H Me
Fe(CO)3
O
OX
H Me
Fe(CO)3
O
Ph
OH
21 X: O, NBn 22
(2) HF/pyridine
(1) BF3·OEt2, PhCHO, CH2Cl2, –78 °C
dr > 93 : 7 66–81%
OTMSX
HMe
Fe(CO)3O
Lower face
HPh
OF3B
Scheme 1.11 Asymmetric induction imparted by chiral π-allyltricarbonyl iron complexes inMukaiyama aldol reactions.
As the iron lactone and lactam (22) can be easily decomplexed to afford a richarray of stereodefined derivatives, this reaction may represent a powerful tool to therapid construction of highly functionalized systems under remote stereocontrol. Forinstance, total synthesis of (−)-gloeosporone (23) commenced with the addition ofsilyl enol ether from methyl ketone (24) to benzyloxypropanal, which afforded aldol(25) as a single diastereomer in a 63% yield (Scheme 1.12) [24].
1.2.4Chiral Aldehydes
The asymmetric induction of chiral aldehydes in Mukaiyama aldol reactions ismuch more important and has stimulated the formulation of increasingly morerefined models to predict the π-facial selectivity in nucleophilic additions to thecarbonyl bond [25]. Therefore, the influence of α- and β-substituents has receivedparticular attention and is described in detail in the following sections.
1.2.4.1 1,2-Asymmetric InductionPioneering studies on acyclic stereoselection established that Mukaiyama acetatealdol additions of enolsilane derivatives (26) and (27) to chiral α-methyl aldehydes
OO
H C5H11
Fe(CO)3O
OO
H C5H11
Fe(CO)3O
OH
24 25
(1) TMSOTf, Et3N, CH2Cl2, 0 °C
63%
(2) BF3·OEt2, BnOCH2CH2CHO
CH2Cl2, –78 °C(3) HF/pyridine OBn
OO
O
OC5H11
OH
23 (−) Gloeosporone
Scheme 1.12 Synthesis of (−)-gloeosporone.
1.2 Mukaiyama Aldol Reaction 9
(28) proceeded with high diastereofacial selectivity to favor 3,4-syn aldol adducts(29) (Scheme 1.13) [26].
As expected, the 1,2-asymmetric induction of such aldehydes was eroded whenR2 was sterically similar to the α-methyl. The challenge posed by these transfor-mations can be met by using more bulky nucleophiles, as has been observed inthe aldol additions of enolsilanes (26), (27), and (30) to 2-methyl-3-phenylpropanal(Scheme 1.14). The stereochemical outcome of these reactions shows that enhance-ment of the steric hindrance of R1 and SiR3 groups gives the corresponding 3,4-synaldols (31) in higher diastereomeric ratios [26, 27]. A parallel improvement canalso be attained by employing more bulky Lewis acids, but steric influences mustbe analyzed carefully because some combinations of bulky nucleophiles and Lewisacids do not provide the expected results [27].
The Felkin–Anh model [25, 28] is usually invoked to account for the asymmetricinduction observed in the Mukaiyama aldol additions to these chiral α-methylaldehydes. Thus, once the methyl group has been identified as the medium sizegroup, the major 3,4-syn diastereomer is obtained by bringing the enolsilane close tothe face of the C=O bond in which the steric interactions between the nucleophileand the α-substituent (H vs Me) are weaker (X in Scheme 1.15).
The total synthesis of borrelidin (32) reported by Theodorakis contains a goodexample of stereocontrol based on the asymmetric induction imparted by suchchiral aldehydes [29]. As represented in Scheme 1.16, the Mukaiyama aldol additionof silyl ketene acetal (27c) to α-methyl aldehyde (33) produced the desired ester (34)
R1
OTBS
+ HR2
O
R1
O OH
R21 equiv BF3·OEt2
CH2Cl2, –78 °C
2926 R1: Me, t-Bu,
27 R1: OMe, Ot-BuR2: Ph, PhCH=CH, Cy
28dr 91 : 9 to 97 : 3 68–81%
34
3,4-syn
Scheme 1.13 Asymmetric induction imparted by chiral α-methyl aldehydes in Mukaiyamaaldol reactions.
R1
OSiR3
+ 34
H Ph
O
R1
O OH
Ph
Me
MeO
t-BuO
t-BuS
t-BuS
57 : 43
62 : 38
71 : 29 88
85 : 15
93 : 7
R1 dr
TBS
TBS
TBS
TBS
TIPS
SiR3
72
78
43
78
yield (%)26, 27, 30 31
26a
27a27b
30a30b
Enolsilane
1 equiv BF3·OEt2
CH2Cl2, –78 °C
28d
Scheme 1.14 Mukaiyama aldol additions to (R) 2-methyl-3-phenylpropanal.
10 1 Stereoselective Acetate Aldol Reactions
Me
H
R2
H
OH
Me
R2
H
O
Nu Nu
R1
OSiR3
Nu :
MLn MLn
R1 R2
O OH
R1 R2
O OH
34
34
3,4-syn3,4-antiXXI
Scheme 1.15 The Felkin–Anh model for Mukaiyama aldol additions to chiral α-methyl alde-hydes.
PMBO
OTBS+
H
O O
TBSOH
OMEM
OH O
TBSOH
OMEM
O
PMBO
27c33
34
BF3·OEt2, 4 Å MS, THF, –78 °C dr 80 : 20 95%
HO
O
O
CN
HO
CO2HH
32 Borrelidin
Scheme 1.16 Synthesis of borrelidin.
as a 80 : 20 mixture of diastereomers in a 95% combined yield, which demonstratesthe π-facial selectivity provided by the α-stereocenter of aldehydes of this kind [30].
The substitution of the methyl group by a heteroatom affects these transforma-tions dramatically. Indeed, a tenet in asymmetric synthesis states that nucleophilicadditions to chiral aldehydes bearing an α-heteroatom attain outstanding levels ofstereocontrol provided that the reaction is carried out under conditions in whichchelate organization is favored. In this context, the Cram model [25, 31] accountsfor the stereochemical outcome of chelate-controlled Mukaiyama aldol reactions.According to this model, the appropriate choice of the Lewis acid and the protect-ing group of α-hydroxy aldehydes permits the formation of stable five-memberedchelated complexes and gives the corresponding 3,4-syn aldol adducts in a highlydiastereoselective manner, presumably through an open transition state in whichthe nucleophile approaches the less hindered face of the chelated carbonyl group(Scheme 1.17).
This highly reliable and powerful element of stereocontrol has been widelyexploited in the synthesis of natural products. For instance, Sunazuka and Omuraused a chelate-controlled Mukaiyama aldol reaction for the total synthesis of anepimer of guadinomine C2 (35). As shown in Scheme 1.18, addition of silyl keteneS,O-acetal (36a) to chiral α-OPMB aldehyde (37) in the presence of 1.1 equiv ofTiCl3(i-PrO) gave 3,4-syn aldol (38) with exceptional diastereoselectivity in 64%yield [32].
1.2 Mukaiyama Aldol Reaction 11
R1
OSiR3
R1 R2
O OH
OPG
34
3,4-syn
HR2
O
OPG
MLn
O
OPGH
R2
MLn
OPG
HR2
H
O
Nu
MLn
Scheme 1.17 Cram model for Mukaiyama aldol additions to chiral α-hydroxy aldehydes.
EtS
OTMS
+ OTBSH
O
OPMB
OTBS
OH
OPMB
O
EtS
36a 37
CH2Cl2, –78 °C
1.1 equiv TiCl3(i-PrO)
38dr > 99 : 1 64%
NHNNH
HN
O
H2N
OH
OH
HN
O
O NH
HN
O
CO2H
35 3′S Epimer of guadinomine C2
Scheme 1.18 Synthesis of (3′S) epimer of guadinomine C2.
Moreover, Forsyth reported that the addition of mild Lewis acid MgBr2· OEt2
to a mixture of chiral silyl enol ether (39) and α-OPMB aldehyde (40) triggered asmooth aldol reaction that furnished 3,4-syn aldol (41) as a single diastereomer in79% yield, which was further elaborated to a hapten for azaspiracids (Scheme 1.19)[33]. A very similar transformation was also reported by Evans [34, 35].
Hapten of azaspiracids
+
39
N3
OTMS
H
O
OPMB
OTBS TMS
40
12 equiv MgBr2·OEt2CH2Cl2, –78 to –25 °C 79%
OH
OPMB
OTBS TMSO
N3
41
OO
O CO2H
O
H
HN
H
Scheme 1.19 Synthesis of a hapten for azaspiracids.
12 1 Stereoselective Acetate Aldol Reactions
In the absence of chelated intermediates, nucleophilic additions to chiral alde-hydes possessing an α-heteroatom are currently explained by the polar Felkin–Anh[36] and Cornforth models [37], which apply to conformations XII–XV arisingfrom rotation about the C1–C2 bond of the aldehyde (Scheme 1.20) [25]. Thepolar Felkin–Anh model is based on the premise that staggered transition statespositioning the C–X bond perpendicularly to the carbonyl bond are preferred((1) in Scheme 1.20). In turn, the Cornforth model embraces the assumption thatelectrostatic effects are instrumental in dictating a nearly antiparallel relationshipbetween the carbonyl and the C–X bond ((2) in Scheme 1.20). Then, the stereo-chemical outcome of these additions depends on the steric interactions betweenthe nucleophile and the remaining α-substituents in alternative transition states.Application of both models to Mukaiyama aldol reactions predicts the preferentialformation of 3,4-anti aldol adducts.
Most of the aldol reactions involving such aldehydes proceed in accordance withthese expectations, but systematic studies on the addition of enolsilanes (42) toα-chloro, α-hydroxy, and α-amino aldehydes (43–45) revealed that their diastere-oselectivity is dependent significantly on the α-heteroatom and the steric bulk ofnucleophiles (Scheme 1.21) [38–40]. Thus, additions of acetone-derived enolsi-lane (42a) to aldehydes (43) and (44) possessing an electronegative α-heteroatomsuch as chlorine or oxygen afforded the corresponding 3,4-anti aldols (46a)and (47a) (dr 60 : 40 and 82 : 18, respectively), whereas more sterically hinderedpinacolone-derived enolsilane (42c) gave under the same conditions 3,4-syn aldol(46c) or equimolar mixtures of 3,4-anti and syn diastereomers (47c). In turn,N-benzyl-N-tosyl protected valinal (45) always furnished 3,4-anti aldols (48) inmodest to excellent diastereomeric ratios (Scheme 1.21).
In view of these and a few related studies on the influence of bulky Lewisacids, Somfai proposed that N-protected valinal (45) prefers the polar Felkin–Anh
R2
H
X
H
OH
R2
X
H
O
Nu Nu
R1
OSiR3Nu :
MLn MLn
34
34
3,4-anti3,4-synXIIXIII
R1 R2O
X
R1 R2O
X
OH OH
(1)
H
X
R2
H
OR2
X
H
H
O
Nu Nu
R1
OSiR3Nu :
MLn MLn
34
34
3,4-anti3,4-synXIVXV
R1 R2O
XR1 R2
O
X
OH OH
(2)
Scheme 1.20 Models for Mukaiyama aldol additions to chiral aldehydes possessing anα-heteroatom.
1.2 Mukaiyama Aldol Reaction 13
R1
OTMS
+
42 43–45
BF3·OEt2
CH2Cl2, –60 or –78 °C+
Enolsilane Aldehyde X Aldols dr (anti/syn) Yield (%)
42a42b42c
42a42b42c
42a42b42c
Mei-Prt-Bu
Mei-Prt-Bu
Mei-Prt-Bu
R1
43
44
45
ClClCl
OTBSOTBSOTBS
NTsBnNTsBnNTsBn
46a46b46c
47a47b47c
48a48b48c
60 : 4065 : 3516 : 84
82 : 1875 : 2550 : 50
78 : 2293 : 798 : 2
949299
666966
609485
34
34
46–483,4-anti 3,4-syn
H
O
X
OH
X
R1
O OH
X
R1
O
Scheme 1.21 Mukaiyama aldol additions to chiral aldehydes possessing an α-heteroatom.
manifold, which is not seriously affected by the size of the nucleophile ((1) inScheme 1.20) [39]. In turn, Mukaiyama aldol additions to α-chloro aldehyde (43)would proceed essentially through antiperiplanar Cornforth transition state XVIprovided that R1 is small enough to avoid serious steric interactions with chlorine(Scheme 1.22). Facing such deleterious interactions, sterically hindered silyl enolethers would react through antiperiplanar anti-Cornforth transition state XVII. Asimilar rationale could be applied to α-silyloxy aldehyde (44).
1.2.4.2 1,3-Asymmetric InductionMukaiyama aldol additions to chiral α-unsubstituted aldehydes bearing aβ-heteroatom usually proceed with significant levels of 1,3-anti asymmetricinduction [41]. As illustrated in Scheme 1.23, most of the aldol reactions of silylenol ethers (42) with β-hydroxy, β-chloro, and β-azido aldehydes (49) produce the
34
3,4-anti
OH
Cl
R1
O
HO
ClHi -Pr
LA H
H
OTMS
R1
Steric interactions
XVIAntiperiplanar
Cornforth approach
OH
ClHi -Pr
LA
H
H
R1
TMSO
XVIIAntiperiplanar
anti-Cornforth approach
34
3,4-syn
OH
Cl
R1
O
Note: positions of R1 and OTMS can be interchanged
Scheme 1.22 Cornforth model for Mukaiyama aldol additions to (S) 2-chloro-3-methylbutanal.
14 1 Stereoselective Acetate Aldol Reactions
LA
CH2Cl2, –78 °CR1 H R2
OTMS O X
R2
OH X
R1
O
+
3,5-anti 50
3 5
42
R1: i-Pr, t-Bu R2: i-Pr, CH2CH2RX: OBn, OTBS, Cl, N3
49
LA: BF3·OEt2, TiCl4, MeAlCl2
dr 75 : 25 to 98 : 2 60–99%
Scheme 1.23 Asymmetric induction imparted by chiral α-unsubstituted aldehydes bearing aβ-heteroatom in Mukaiyama aldol reactions.
corresponding 3,5-anti aldols (50) in high diastereomeric ratios regardless of thechelating ability of the Lewis acid and the hydroxyl protecting group [42–44].
The stereochemical outcome of these reactions may not be readily interpretedbecause both open-chain and chelation control lead to the same 3,5-anti diastere-omer (50). Thus, Evans proposed, after a systematic and insightful study, a revisedinduction polar model and a chelate-controlled model to account for the high1,3-asymmetric induction provided by such chiral aldehydes [43]. The former isan open-chain model ((1) in Scheme 1.24) derived from several assumptionscommon to the Felkin–Anh analysis for 1,2-asymmetric induction. First, it isassumed that torsional effects dictate that aldehyde transition state conforma-tions adopt a staggered relationship between the forming bond and the aldehydeα-substituents. Second, it is also assumed that the principal diastereomer arisesfrom the reactant-like transition state wherein the β-stereocenter is oriented anti,rather than gauche, to the forming bond because this geometry reduces nonbondedinteractions between the aldehyde α-substituents and the incoming nucleophile.In turn, the chelate-controlled model applies to suitable β-hydroxy-protected alde-hydes able to form stable six-membered chelates, which can subsequently reactthrough transition states involving either boat or half-chair conformations ((2) inScheme 1.24).
R2 H
X OMLn
+ R1
OSiR3 H H
H O MLn
R2HX
X
R2
H
HH
H O
MLn
Nu
R2
X OH
R1
O
35
3,5-anti diastereomer
(1)
R2 H
PGO O
+R1
OSiR3
(2) MO
O C
H
R2Ln O
M CO
R2H
H
PGPGor
R2
PGO OH
R1
O
35
3,5-anti diastereomer
Half-chair Boat
Nu Nu
M
Ln
Ln
Scheme 1.24 Evans models for Mukaiyama aldol additions to chiral α-unsubstituted aldehy-des bearing a β-heteroatom.
